Antibiotic-resistant S. aureus infections are now increasingly encountered in the community. These community-based infections, especially those due to methicillin-resistant S. aureus (MRSA), have occurred in groups without the usual risk factors. There is minimal understanding of how these strains spread and subsequently become established within communities. This remains a critical issue if interventions are to be designed to prevent population level dissemination of community-associated (CA)-MRSA isolates. This study will address the following questions. 1. What pressures are responsible for the pathways of CA-MRSA spread within the community? Patterns of CA-MRSA transmission within the Columbia University Medical Center catchment area, a largely underserved immigrant population, will be identified. The study will use a retrospective, case control study design. lndex cases with a documented CA-MRSA infection and community matched index controls will provide information on both themselves and their egocentric network members. Network information will be supplemented with data collected from potential reservoirs of CA-MRSA within the community (e.g., daycare facilities and schools). Subjects at these sites will be anonymously sampled for colonization/infection with CA-MRSA. The results will be used to create estimates of transmission probabilities for individual, network and community parameters. A mathematical model will then be developed to simulate transmission pathways within the community, as well as investigate potential intervention strategies that might be used to prevent CA-MRSA transmission. 2. Do strains of S. aureus evolve in the community and become more adapted to the environment? We hypothesize that CA-MRSA strains adapt to their environment and become more ecologically fit as they spread. Selected strains prevalent in the community among different subgroups of the population (e.g., children at daycare) will undergo genetic analysis using comparative total genome sequencing. Mutations that might enhance fitness will be screened using parameters such as growth rate, adherence to different tissue surfaces and survival on environmental surfaces. Screens for the fitness mutations will then be carried out on all S. aureus strains collected from the community. This proposal examines the spread of CA-MRSA in an inner city population. Our recently completed CDC study demonstrated that the community is interested and willing to participate in these types of investigations. Unlike other communities in the United States, CA-MRSA has only recently begun to emerge as a prominent pathogen in this community so that transmission studies are still possible, before CA-MRSA becomes endemic. Finally, this investigation is an innovative integration of diverse research methods including social network data collection strategies, molecular epidemiology, genetic strain analysis and mathematical modeling to address this pressing issue. The end result should be a more comprehensive understanding of CA-MRSA transmission and the intervention strategies that are most likely to be successful in a community setting.